The goals of Project 2 are to define the natural history and biological substrate of age-associated cognitive decline in humans and to distinguish these features from those occurring in Alzheimer's disease (AD). To this end, we plan to characterize age-related alterations in memory and cognition in a cohort of elderly nondemented subjects in the Baltimore Longitudinal Study of Aging and to analyze neuropathological/neurochemical changes in the brains of these and other individuals, ranging in age from the second to the ninth decades. In these brains, we will map the distribution of pathology in the amygdala, hippocampus, dorsomedial nucleus of the thalamus, and prefrontal cortex - - anatomical structures known to play important roles in memory and learning, cognitive functions that decline in older individuals. Combining classical and new techniques, we will first determine the course of development of senile plaques and neurofibrillary tangles. subsequently, we will examine relationships between expression of the beta-amyloid precursor protein gene and neurofilament genes and their proteins in the development of plaques and tangles. To determine whether nerve cells degenerate and die or whether their sizes decrease with age, we will use computerized morphometry to analyze selected cell populations in hippocampus and neocortex. In parallel, to probe a functional parameter of neurons, we will measure age-associated alterations in levels of neurotransmitter markers. Finally, we plan to compare the distribution of abnormalities that occur in the brains of neuropsychologically characterized, nondemented aged individuals to patterns of changes that occur in subjects with AD. This comparison should yield useful information to delineate pathogenetic hypotheses for AD and, at the same time, to allow more satisfactory definition of diagnostic criteria useful for separating the pathology of aging from that of AD. Thus, Project 2 will provide insights into the nature and biological substrate of cognitive decline in aging, will offer clues to the pathogenesis of degenerative processes that occur in aging, and will clarify boundaries between normal aging and AD.